Pharmacology, Toxicology and Environmental Health Commons^™

The Role Of Human Dopamine Transporter Threonine 261 And Serine 262 In Amphetamine Regulation Of Transporter Function And Surface Expression, Sina Abdollahi

Theses and Dissertations

Amphetamine (AMPH) has been used clinically and recreationally around the world for years. A 2021 study reports a 67.5% rise in AMPH use from 2010-2017 across all fifty states. Study also shows that 30% of patients with AMPH-induced psychosis end up with primary psychosis over time. AMPH works by inhibiting monoamine (Norepinephrine (NE), Serotonin (5-HT), and Dopamine (DA) reuptake followed by triggering transporter mediated monoamine release and consequently increases monoamine concentrations in extracellular synaptic space. AMPH also works as a substrate for monoamine transporters, enters the neuron, and once its inside the neuron, it will prevent the storage of monoamines …

Identification Of The New Synthetic Opioid Bucinnazine And Its Metabolites Using Liquid Chromatography Tandem Mass Spectrometry (Lc-Ms/Ms), Karissa N. Resnik

Master of Science in Forensic Science Directed Research Projects

In the past 20 years, the rate of opioid use increased drastically in the United States. The country has experienced an enormous number of deaths caused by opioid overdose, opioid use disorder (OUD), as well as other harms as a consequence of the high numbers of opioid prescriptions. Fentanyl, a well-known synthetic opioid, has been a contributor to the opioid crisis since 2013 due to its popularity in clinical and illicit use. It has a high potency, which makes it an effective analgesic but a dangerous illicit substance. A new synthetic opioid, bucinnazine, has recently become a new black-market opioid …

Mechanisms And Treatment Of Pain-Depressed Behavior In Male And Female Mice, Clare M. Diester

Theses and Dissertations

One of the largest discrepancies between preclinical and clinical assessment of pain and analgesia is the type of behavioral endpoint used. Although most preclinical research has historically focused on drug effectiveness to block reflexive withdrawal behaviors stimulated by a noxious stimulus, increasing evidence shows that drug-induced restoration of pain-depressed behaviors provides increased clinical translation with decreased susceptibility to false-positives. Accordingly, the first portion of this dissertation designed a behavioral battery that featured pain-depressed behaviors as well as more conventional pain-stimulated behaviors for testing candidate analgesics in male and female mice. The main findings are as follows. (1) Intraperitoneal injection of …

Using Molecularly Imprinted Polymers For The Selective Extraction Of Analytes, Haley A. Mulder

Theses and Dissertations

Sample preparation is a critical steps in bioanalysis. Traditional methods such as solid-phase extraction and liquid-liquid extraction are laborious and ultimately incapable of properly separating target analytes from matrix and interferents. The co-extraction of these components interferes with the analytical instrument’s ability to properly detect and quantitate analytes. Molecularly imprinted polymers (MIPs) are synthetic polymers that have been “imprinted” with a template analyte in a co-polymer system. MIPs are capable of selectively extracting analytes from complex biological matrices and can be employed in off-line, benchtop extractions or for on/in-line instrument extractions. MIPs offer faster and more selective sample preparation, leading …

Modulating Ketamine’S Locomotor Activating And Reinforcing Effects Through Drug Combinations, Tegshjargal Baasansukh

Theses and Dissertations

Major Depressive Disorder (MDD) affects approximately 280 million people worldwide. The standard of care for pharmacological treatment of MDD has been monoaminergic antidepressants (MAA). However, MAAs have serious clinical limitations including a relatively slow onset of action and up to 40% of patients failing to respond and being diagnosed as “treatment resistant”. Ketamine, an N-methyl-D-aspartate antagonist, was originally approved for use as an injectable anesthetic. In addition, ketamine has been shown to rapidly improve depressive symptoms in patients with treatment resistant depression. In 2019, (S)-ketamine was approved as a nasal spray (Spravato®) for patients with MDD and treatment-resistant depression in …

Behavioral Screening And Chiral Bioanalysis Of Emerging Stimulant-Type Drugs In Rats, Tyson R. Baird

Theses and Dissertations

The epidemic of drug use in the United States and elsewhere in the world has resulted in tragic loss of life and substantial economic costs. Novel psychoactive substances (NPS) are one of the contributors to this problem, and the lack of information about many of these drugs compounds their risk. This dissertation proposes a strategy to use intracranial self-stimulation (ICSS) as a behavioral screening tool to assess emerging drugs of abuse for their abuse potential in order to generate a proactive threat assessment. A series of stimulant-type drugs including methcathinone, α-pyrrolidinohexanophenone (α-PHP), cocaine, and the phenyltropane analogs of cocaine WIN35428 …

Survival, Growth, And Characterization Of Microbes In E-Liquids, Jessica Bunn

Master of Science in Forensic Science Directed Research Projects

Health risks associated with the use of e-cigarettes have become a concern in the last ten years, including the inhalation of volatile organic compounds, trace heavy metals, and cancer-causing agents. An additional, but poorly characterized health threat for e-liquids is the potential for bacterial contamination since the presence of pathogenic organisms can potentially cause disease from the inhalation of the microbes into the lungs. This work aims to investigate microbial growth and survival within the e-liquid matrix. Bacillus cereus T. strain and Escherichia coli were the chosen organisms for analysis of growth by absorbance, survival by viable plate counts, and …

Analysis Of Ethanol Aerosolized In An Electronic Cigarette By Headspace Gas Chromatography-Flame Ionization Detector (Gc-Fid) And Particle Size Separation, Erica R. Sales

Master of Science in Forensic Science Directed Research Projects

Electronic cigarettes (e-cigs) were designed as a healthier alternative nicotine delivery system, and involve the heating of e-liquids. These are composed of propylene glycol, vegetable glycerin, flavoring agents, and nicotine. Recently, ethanol has been identified as an unlabeled ingredient. The health consequences are currently unknown.

The purpose of this study is to quantify the amount of ethanol present in an aerosol cloud and to determine the size of the ethanol particles. A SubOx Mini-C e-cig was used. For ethanol quantification, the e-cig was attached to a Buchner Flask containing 150mL of deionized water, The system was attached to a vacuum …

Influence Of 2,5-Dimethoxy-4-Iodoamphetamine (Doi) On Ethanol Preference And Consumption In C57bl/6 Male Mice, Alaina M. Jaster, Sam Gottlieb, Michael Miles, Javier González-Maeso

Graduate Research Posters

Substance use disorders (SUD) account for a large number of mental health diagnosis in the United States and around the world. Approximately 13.6 million adults 26 or older and 5.1 million young adults (ages 18-24) battled with a SUD in 2017. Alcohol Use Disorder (AUD) alone effects nearly 6% of the adult population within the United States. This creates a substantial burden on the individual, with alcohol being the third-leading cause of preventable death in the United States. Few treatments for AUD exist, with no new FDA-approved therapeutic treatments within the last 15 years. Additionally, the limited treatments we do …

Investigating Cannabinoid Type-1 Receptor (Cb1r) Positive Allosteric Modulators (Pams) In Mouse Models Of Overt Cannabimimetic Activity, Subjective Drug Effects, And Neuropathic Pain, Jayden Elmer

Theses and Dissertations

Chronic pain affects between 20 and 30 percent of the adult population in western countries and represents a wide array of specific etiologies (Berge, 2011). Neuropathic pain secondary to traumatic nerve injury, chemotherapeutic toxicity, or diseases (e.g., diabetes mellitus) is often refractory to conventional analgesics, with patients receiving less than 50% pain relief compared to placebo (Finnerup et al. 2010). The endocannabinoid system has shown potential as a therapeutic target for neuropathic pain wherein CB1 agonism via administration of exogenous agonists or pharmacological blockade of endocannabinoid catabolic enzymes exhibits efficacy in reversing allodynia in the chronic constriction injury (CCI) model …

Pharmacophoric Evaluation Of 5-Ht2a And 5-Ht2b Serotonin Recpeptors, Prithvi Hemanth

Theses and Dissertations

Serotonin (5-HT) receptors represent a class of receptors involved in a variety of physiological processes including regulation of mood, perception, cognition, appetite, and heart function, and thus serve as drug targets of several drugs such as antipsychotic agents, hallucinogenic drugs, and appetite suppressant drugs. Due to the structural similarity of certain 5-HT receptor subtypes, particularly 5-HT₂ receptors (5-HT_2A, 5-HT_2B receptors) determination and refinement of pharmacophore models of these receptor subtypes can greatly improve the therapeutic efficacy of drugs that target them.

The goals of this study were to define and/or refine existing pharmacophore models for 5-HT …

Dendrimer-Based Antibiotics For The Treatment Of Bacterial Biofilm In Cystic Fibrosis (Cf), Younan Ma

Theses and Dissertations

Pseudomonas aeruginosa (PA) is the predominant pathogen in chronic lung infections of cystic fibrosis (CF) patients. The most important mechanism of adaptation of PA to host defense and antibiotic treatment is the formation of biofilms within the mucus layer covering the lung bronchi. The effectiveness of antibiotics such as aminoglycosides is significantly attenuated by their limited penetration through thick mucus and embedded biofilm matrix in patients’ lung. Inhaled tobramycin (Tobra), which is the most commonly used antibiotics in the treatment of PA infections for CF patients, is usually found to be in very high concentration in patients’ lung, and yet …

Interclass Gpcr Heteromerization Affects Localization And Trafficking, Rudy Toneatti

Theses and Dissertations

Class A serotonin (5-hydroxytryptamine) 2A (5-HT_2AR) and class C metabotropic glutamate 2 receptors (mGluR2) are seven transmembrane receptors (7TMRs or G protein-coupled receptors – GPCRs) involved in multiple neuropsychiatric disorders including schizophrenia. Previous findings from our laboratory reported that 5-HT_2AR and mGluR2 are dysregulated in the prefrontal cortex of patients suffering from this psychiatric condition, although 5-HT_2AR’s expression was recovered in antipsychotic-medicated patients. Genome-wide association studies on schizophrenia reported that endosomal trafficking that regulates cell surface abundance of another 7TMR implicated in this disease (dopamine D2 receptor) can be altered. Ligand-activated receptors, including the …

The Cb1 Receptor Positive Allosteric Modulator, Zcz011, Attenuates Naloxone-Precipitated Withdrawal Signs In Oxycodone-Dependent Mice And Inhibits Small Intestinal Transit In Mice, Julien Dodu

Theses and Dissertations

The endogenous cannabinoid system tightly regulates a myriad of physiological and pathophysiological functions. Effects of cannabinoids in ameliorating opioid withdrawal signs has been known for decades. Naloxone precipitates several withdrawal signs (e.g., diarrhea, weight loss, jumps, paw flutters, and head shakes) in opioid dependent rodents. ∆⁹-tetrahydrocannabinol (THC) has been shown to ameliorate opioid withdrawal in mice through the activation of cannabinoid type-1 (CB₁) receptors. Inhibition of the endocannabinoid degradative enzymes also attenuates these withdrawal signs (i.e., diarrhea, weight loss, jumps, paw flutters, and head shakes) in opioid-dependent mice. Specifically, inhibition of fatty acid amide hydrolase (FAAH), …

Nebulizer-Based Systems To Improve Pharmaceutical Aerosol Delivery To The Lungs, Benjamin M. Spence

Theses and Dissertations

Combining vibrating mesh nebulizers with additional new technologies leads to substantial improvements in pharmaceutical aerosol delivery to the lungs across therapeutic administration methods. In this dissertation, streamlined components, aerosol administration synchronization, and/or Excipient Enhanced Growth (EEG) technologies were utilized to develop and test several novel devices and aerosol delivery systems. The first focus of this work was to improve the poor delivery efficiency, e.g., 3.6% of nominal dose (Dugernier et al. 2017), of aerosolized medication administration to adult human subjects concurrent with high flow nasal cannula (HFNC) therapy, a form of continuous-flow non-invasive ventilation (NIV). The developed Low-Volume Mixer-Heater (LVMH) …

Novel Strategies To Overcome Carboplatin Resistance In Triple Negative Breast Cancer Using Patient Derived Xenografts, Mohammad A. Al Zubi

Theses and Dissertations

Triple-negative breast cancer (TNBC) patients have a poor prognosis and rely on chemotherapeutic treatment as standard of care. Often, they develop chemotherapy resistance, which leaves them without more therapeutic options, like targeted therapy. New models have been developed to test targeted inhibitors in human tumors, and they are known as patient-derived xenografts (PDX). These tumors are obtained from patients, then established and maintained in mice where they areused for tumor studies. In this work, we characterized 14 PDXs for their primary tumor growth rate and investigated metastatic propensity using spontaneous and experiment metastasis models. We utilized RNA-sequencing to characterize contributions …

Environmental Governance For Whom? Examining The Political, Institutional, Fiscal, And Legal Determinants Of State Environmental Agency Budget Policy In The Us, Andrew R. Duggan

Theses and Dissertations

Budgets are a prospective tool of governance, and appropriations are a planning vehicle reflecting: bureaucracies’ values, complex interactions, collective preferences, political influences, and available resources. Research spanning 30 years finds that environmental pollution is a key determinant of environmental budgets in the US, though myriad factors, actors, and subsystems are important to consider. Due to federalism and devolution of responsibilities and authorities, environmental governance falls largely to the states. While the dynamics that shape state environmental budget policy have received scholarly interest, theoretically-driven examinations of environmental appropriations remain limited within the public budgeting and environmental policy literature.

Using panel data …

Characterization Of Cardiovascular Risk Factors People Living With Hiv In A Veteran Population, Veronica Taylor, Joe Castillo, Daniel Tassone Pharmd, Bcps

Graduate Research Posters

Background: CVD is the leading cause of death in PLWH. HIV positive individuals have a 1.5-2-fold greater risk of CVD compared to uninfected individuals, even if complete viral load suppression is achieved. HIV-associated CVD has tripled over the past 20 years, yet scant data is available describing this population. We have characterized CVD risk factors and treatment in PLWH in order to assess and improve cardioprotective treatment.

Methods: A retrospective EMR review was conducted for HIV positive patients enrolled at the McGuire VAMC between 12/2018 and 12/2019. Patients were excluded if labs were older than one year from follow-up. …

Pharmacology Of Fentanyl-Related Substances In Mice Reveals Potential Therapeutics With Improved Protective Indices, Neil B. Varshneya

Theses and Dissertations

Fentanyl-related substances constitute a class of compounds that were originally developed in the latter half of the 20th century as combination analgesic-anesthetic agents. Today, many of these compounds have emerged in the recreational drug marketplace as adulterants to heroin, counterfeit prescription pills, and even as standalone products designed to circumvent drug control laws. The objective of this dissertation was to identify the structural determinants of fentanyl analogs that could affect the potency and efficacy for eliciting their therapeutic and toxic effects to identify candidates of potential therapeutic interest. To accomplish this objective, thirty-eight fentanyl-related substances, in addition to the MOR …

Epigenetic Regulation Of Drug Metabolizing Enzymes In Normal Aging, Mohamad M. Kronfol

Theses and Dissertations

Geriatric populations are at a higher risk for adverse drug reactions (ADRs). This may be partly due to changes in drug metabolism in old age, but the underlying mechanisms are poorly understood. Prior research in humans and mice has shown age-associated changes to the expression of several genes involved in drug metabolism. Furthermore, studies of human blood showed that epigenetic regulation of genes encoding drug metabolizing enzymes change with age. However, it is unknown if genes in the liver are similarly affected. Therefore, we hypothesize that genes encoding drug metabolizing enzymes may show differential epigenetic regulation in the liver with …

Model-Based In-Vitro Pk/Pd Profiling Of Novel Synthetic Allosteric Effectors Of Hemoglobin (Aeh) As Potential Sickle Cell Disease (Scd) Therapeutics, Xiaomeng Xu

Theses and Dissertations

Introduction: Allosteric effectors of hemoglobin (AEH) represent a class of synthetic aromatic aldehydes that transiently form covalent interactions (Schiff-base) with hemoglobin (Hb) to form Hb-AEH adduct, preventing the HbS polymerization and sickling of red blood cells (RBC). The overall objective of this research was to aid in the optimization of novel AEH by understanding their target-site disposition of AEH in relevant biological matrices, e.g., HbA solution, whole blood (WB) and human liver cytosol (HLC), a surrogate of aldehyde dehydrogenase (ALDH)-mediated oxidative metabolism.

Methods: A “universal” HPLC-UV/Vis assay method was developed for the quantitation of HbA-AEH adduct for chemically …

Exosomes As Systemic Mediators Of Nanotube Induced Neurotoxicity, Christopher G. Canal

Theses and Dissertations

Extra-pulmonary effects of nanoparticle inhalation have been well documented; however, mechanisms for conveying peripheral bioactivity remain elusive. Recent studies point to indirect molecular mediators shed into the circulation. Protein and lipid alternatives to cytokines or chemokines have been proposed, yet the diversity among responses suggests a broader assemblage of factors. Recently we have proposed proteolytic fragment peptides as an additional source of bioactivity, which interestingly were significantly associated with exosomal proteins after enrichment analysis. Here we tested whether modeled exposure to multi-walled carbon nanotubes (MWCNT) could alter the composition and bioactivity of circulating exosomes. Male C57BL/6 mice were exposed by …

A Pharmacokinetic Model Of Lead Absorption And Calcium Competitive Dynamics, Anca R. Radulescu

Biology and Medicine Through Mathematics Conference

No abstract provided.

Chemical Characterization Of Pseudognaphalium Obtusifolium By Gas Chromatography - Mass Spectrometry (Gc-Ms) To Assess Potential Therapeutic Phytochemicals And Toxicological Concerns Using Simulated Use Conditions, Regina Ballentine

Theses and Dissertations

Chemical Characterization of Pseudognaphalium obtusifolium by Gas Chromatography – Mass Spectrometry (GC-MS) to Assess Potential Therapeutic Phytochemicals and Toxicological Concerns Using Simulated Use Conditions

By Regina Ballentine

Virginia Commonwealth University, 2019

Director: Sarah C. Rutan, Professor, Department of Chemistry

Currently, there is an increasing demand for natural therapies and herbal products to treat various ailments. It is generally believed that natural therapies have fewer side-effects than traditional western medicine; however, they are often used in different strengths and formulations without consistency of the levels of target compounds or knowledge about toxicity. Due to this growing trend, a comprehensive chemical evaluation …

The Analgesic-Like Properties Of Alcohol In Animal Models Of Chronic Pain, Bradley Neddenriep

Theses and Dissertations

Chronic pain and excessive alcohol consumption are individually problems in our society today. Alcohol Use Disorder (AUD) affects 15.1 million adult Americans each year. Chronic pain affects over 100 million people annually in the United States. However, there is growing evidence suggesting that these two conditions can often be interrelated with chronic pain increasing consumption of alcohol, and excessive alcohol consumption increasing pain that leaves a feedback cycle trapping millions of patients in an ever worsening spiral. Large population-based studies show an association between pain and alcohol abuse, suggesting a link between increased alcohol use and reduced pain. While rodent …

Structure-Activity Relationship Studies Of Synthetic Cathinones And Related Agents, Rachel A. Davies

Theses and Dissertations

Synthetic cathinones and related agents represent an international drug abuse problem, and at the same time an important class of clinically useful compounds. Structure-activity relationship studies are needed to elucidate molecular features underlying the pharmacology of these agents. Illicit methcathinone (i.e., MCAT), the prototype of the synthetic cathinone class, exists as a racemic mixture. Though the differences in potency and target selectivity between the positional and optical isomers of synthetic cathinones and related agents have been demonstrated to have important implications for abuse and therapeutic potential, the two MCAT isomers have never been directly compared at their molecular targets: the …

Molecular Targets Of Psychedelics And Their Role In Behavioral Models Of Hallucinogenic Action, Hiba Z. Vohra

Theses and Dissertations

Psychedelics are a subset of hallucinogenic drugs that exert their characteristic effects through agonist activity at the serotonin receptor 2A (5-HT_2A). In this study, I aimed to characterize the modulatory role of the metabotropic glutamate subtype 2 receptor (mGluR2) in the 5-HT_2A-specific rodent model of hallucinogenic action, head-twitch response (HTR). Secondly, I aimed to explore if 5-HT_2A agonist-induced deficits in prepulse inhibition (PPI) of the startle response, an additional model of hallucinogenic action, could be produced in mice. Though 5-HT_2A agonist-induced PPI deficits, which represent interruptions in normal sensorimotor gating, have been described in …

An Investigation On The Role Of Β-Arrestin 2, Protein Kinase C And Sex On The Mechanism Of Morphine Tolerance In The Mouse Ileum, Karan Hitesh Muchhala

Theses and Dissertations

Opioids such as morphine are frequently used in the clinic to treat pain. However, the perennial bane of chronic opioid use is the rapid development of tolerance to the analgesic effects but delayed development of tolerance to the respiratory depressant and constipating effects. As constipation is one of the most common opioid-related adverse effects in humans, it is important to delineate mechanisms that drive opioid tolerance in the ileum and lack of it in the colon. The overarching goal of this thesis was to investigate mechanisms of morphine tolerance in the ileum by comparing the mechanism of morphine tolerance in …

Effects Of A Heroin Conjugate Vaccine On The Antinociceptive And Abuse-Related Effects Of Heroin In Rats And Monkeys, Kathryn L. Schwienteck

Theses and Dissertations

The increase in heroin use is one factor contributing to the current opioid epidemic in the United States. There are three Food and Drug Administration (FDA) approved medications for the treatment of opioid use disorder (OUD), and these include agonist (i.e. methadone and buprenorphine) and antagonist (i.e. naltrexone) therapies. Although these medications are effective for some patients, regulatory constraints for agonist therapies limit access and patient compliance for naltrexone is poor. The development of new therapies, such as immunopharmacotherapies, for the treatment of OUD is a priority for the National Institute of Drug Abuse. A heroin immunopharmacotherapy, or vaccine, produces …

Diuretic And Natriuretic Activity Of Faah Inhibition In The Renal Medulla: A Proposed Role Of Palmitoylethanolamide And Its Regulation By Renal Medullary Interstitial Cells, Sara Dempsey

Theses and Dissertations

Hypertension is a critical public health issue worldwide, and in the United States, it is the leading cause of heart disease, stroke, and kidney failure, contributing to more than 1,100 deaths per day. It is proposed that the renal medulla combats increased blood pressure by releasing a neutral lipid from the lipid droplets of medullary interstitial cells, termed medullipin, which induces diuresis- natriuresis and vasodepression. The renal medulla is enriched with fatty acid lipid ethanolamides including the endocannabinoid anandamide (AEA), palmitoylethanolamide (PEA), and oleoylethanolamide (OEA), along with their primary hydrolyzing enzyme fatty acid amide hydrolase (FAAH). Our lab is investigating …